The impact of adipokines hormones on HCV life-cycle

P Behrendt; J Dörrbecker; E Steinmann; K Hügging; N Menzel; E Grabski; M Rogalska-Taranta; S Pfaender; U Kalinke; H Wedemeyer; MP Manns; T Pietschmann

doi:10.1055/s-0033-1361056

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

The impact of adipokines hormones on HCV life-cycle

P Behrendt ¹, J Dörrbecker ², E Steinmann ², K Hügging ², N Menzel ², E Grabski ², M Rogalska-Taranta ¹, S Pfaender ², U Kalinke ², H Wedemeyer ¹, MP Manns ¹, T Pietschmann ²

¹Medical School Hannover, Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
²Twincore Institute, Center for Experimental and. Clinical Infection Research, Hannover, Germany

Abstract

Obesity is associated with increased viral load during HCV-infection and non-response to IFN/Ribavirin-based therapy. Fat tissue is known to produce a variety of cytokines and hormones leading to increased levels of pro-inflammatory markers in sera of obese individuals. In this study we assessed the impact of several adipokines on cell-culture derived full-length HCV life cycle.

A few tested hormones showed moderate antiviral activity in vitro (IL-6, TNF-α). However, a promising effect was observed for the adipokine Chemerin.

Chemerin is a recently discovered hormone that is mainly expressed by fat-tissue and the liver. It is elevated in obese compared to lean individuals, ˜300 ng/ml to ˜200 ng/ml respectively, and has been recently described for the first time (2005). By binding to its main receptor – the G-protein-coupled Chemokine-like receptor 1 (CMKLR1) -, which is mainly expressed by macrophages, pDCs/mDCs and NK-cells, Chemerin serves as a chemo-attractant. However, little is known about its impact on non-immune cells.

In cell-culture derived full-length HCV screen we observed an antiviral effect of this hormone (IC90 at 1000 ng/ml) in vitro. We excluded a modulation on HCV-entry using HCV-pseudoparticles and confirmed an inhibition of replication with subgenomic replicons of two different HCV genotypes (1a, 2a). Treatment of the target cells with Chemerin prior and post infection with HCV caused a robust inhibition of viral replication. Interestingly, the hormone failed to inhibit replication of vesicular stomatitis virus as well as coronavirus.

Modulation of CMKLR1 (overexpression- and knock-down experiments) did not alter the inhibition of viral replication by Chemerin in Huh7.5 cells. The same was observed for two other receptors (GPR1, CCRL2), which have been recently reported to bind Chemerin and thereby induce only minor signaling events.

Currently, we are performing phosphokinase-arrays as well as transcriptomic-analysis in order to elucidate the mode of action of Chemerin on Huh7.5 cells.

Additionally, we performed co-culture experiments of either pDCs or NK cells with HCV-transfected Huh7.5 cells and observed no alteration of immune cell function under Chemerin-treatment.

Overall, we showed for the first time that Chemerin causes and antiviral status within Huh7.5 cells that significantly inhibited viral replication. This effect is not caused by the interaction of Chemerin with its previously described receptor (CMKLR1, GPR1, CCRL2). We are currently investigating the mode of action of this exciting hormone in more detail.